Building an Enhanced Analytical Toolbox for In-vivo Predictive Dissolution Justin Pennington, Sanjay Patel, Jesse Kuiper, Amanda Mann, Andre Hermans PSCS-Analytical Sciences
Outline – Determination of Dissolution Mechanism – 1x Bio-Relevant Dissolution – Transfer Model for Weakly Basic APIs – Future of Dissolution Methodology (Time Permitting)
Outline – Determination of Dissolution Mechanism – 1x Bio-Relevant Dissolution – Transfer Model for Weakly Basic APIs – Future of Dissolution Methodology (Time Permitting)
The Power of the Dissolution Test Dissolution is the only product test that truly measures the effect of formulation and API physical properties on the rate of drug solubilization Dissolution = disintegration + intrinsic dissolution K 1 K 2 K 3 API SOLUBILIZED TABLET GRANULES PARTICLES DRUG Disintegration Solubilization
Determination of Dissolution Mechanisms • The determination of dissolution mechanism is mainly accomplished through visual observations. • Erosion Based: – An observable “dry core” throughout the dissolution experiment. – May swell to some degree and granules may flake off – Measured Dissolution rate is relatively unaffected by granule properties • Granule Based: – Rapid release of granules into the bulk solution – Granules will typically be large and will decrease in size over time – Tend to disintegrate rapidly and are highly affect by changes to granulation properties
Dissolution Mechanism Summary • The extent and location of dissolution of a pharmaceutical product is critical to ensure proper drug delivery to the patient and can greatly affect the observed pharmacokinetics for a drug candidate. • While there are many factors at play to consider when evaluating dissolution, the general manner in which a dosage form dissolves can be generalized in the following matter. K 1 K 2 K 3 API SOLUBILIZED TABLET GRANULES PARTICLES DRUG Disintegration Solubilization Note: Any factors (k) can be either rate limiting or potentially negligible.
Bioavailability Depends on Dissolution • Dissolution is the best surrogate for bio-performance if IVIVC can be established. • It enables selection/ rank ordering of formulation candidates in early development without the need to perform actual in vivo (animal or human) studies significantly accelerating development
Outline – Determination of Dissolution Mechanism – 1x Bio-Relevant Dissolution – Transfer Model for Weakly Basic APIs – Future of Dissolution Methodology (Time Permitting)
Selection of Dissolution Conditions Biorelevant dissolution can be conducted under different Biorelevant dissolution can be conducted under different sink conditions depending on the purpose of the study. sink conditions depending on the purpose of the study. Dose Relevant Dose Relevant 1x Solubility Limit 1x Solubility Limit • Biorelevant dissolution may be • Standard Biorelevant test conducted at dose relevant • Intended to probe the response of concentration which often exceeds drug dissolution rate to API particle the solubility limit of the most stable size distribution, wettability and API phase in that medium. dispersibility. • This is used to assess the behavior • May be conducted on all parts of the of a metastable API phase under drug product from API and supersaturated condition and the dispersion/extrudate through formulation impact on the kinetics of granules and tablets supersaturation
Dissolution at 1X versus Dose Relevant Concentrations • 1X Solubility Approach Allows Quantitative Comparisons Across Formulation Types Calculated Dissolution at 1X - 5 Calculated Dissolution at Dose ug/mL Drug Solubility, Varying Relevant (40X) - 5 ug/mL Drug PSD Solubility, Varying PSD 6.0 6.0 5.0 5.0 Drug in solution (ug/mL) Drug in solutin (ug/mL) 4.0 4.0 1 um 1 um 3.0 3 um 3.0 3 um 5 um 5 um 2.0 2.0 10 um 10 um 20 um 20 um 1.0 1.0 0.0 0.0 0 50 100 150 0 50 100 150 Time (minutes) Time (minutes)
Practically, What Working at “1X” Means • Using the 5 µ g/mL solubility in FaSSIF example, and the 100 mg dose That’s a lot of FaSSIF! To work at “1X” with a complete 100 mg tablet then would require a • 20,000 mL volume We work with granules (example here, 1/40 th weight of a tablet in 500 • mL faSSIF) or portions of tablets – or pre-disintegrated in SGF 11
1X Dissolution is Readily Modeled If API is dispersed properly and that PSD put into the disso calculation –calc/experiment agree well APIs pre-dispersed prior to putting in FaSSIF - drug added at 1 mg/ml
This Approach Allows Quantitative Comparisons Across Formulation Types Formulation Attribute 1x Dissolution Response API Dispersion in dose Formulations that do this better will have faster rates of dissolution than those that do this poorly Granulation of API Granulation can help with dispersion of particles in dissolution – also over granulation can add additional dissolution rate slowing (increase in ρ term (particle density) Addition of Surfactants Helping wet the particles may improve dissolution rate 13
This Approach Allows Quantitative Comparisons Across Formulation Types Understanding the dissolution rate of well dispersed API particles is the first step in evaluating dissolution performance – as a very well dispersed formulation with very fast granule dissolution will approach dispersed API dissolution rate. 14
Representative 1X Data Comparing Formulation Components 15 API calculated dispersed API “1x Formulation Yardstick” WG granule with surfactant RC granule optimize Tablet
Outline – Determination of Dissolution Mechanism – 1x Bio-Relevant Dissolution – Transfer Model for Weakly Basic APIs – Future of Dissolution Methodology (Time Permitting)
Two-Stage Dissolution During the typical two-stage dissolution, 1X addition of FaSSIF creates sudden pH change for the 2nd stage. This may be especially problematic for weak bases, which may undergo precipitation in the 2nd stage. 250 mL double Formulation concentration (2X) sample (FaSSIF, pH 6.9) Two-stage 30 min 120 min Sample in dissolution 500 mL FaSSIF Sample in Sample in 250 mL SGF 250 mL SGF Sudden increase in pH (1.8 to 6.5) 17
Multicompartment Transfer Model to Predict Dissolution/Precipitation of Weakly Basic Drug Flow rate 5 mL/min 1 micron filter membrane Sink/ Reservoir supersaturation compartment Gastric Intestinal (FaSSIF, pH 7.0) compartment compartment (SGF, 250 mL, 100 rpm) (FaSSIF, 250 mL, 50 rpm) 18
Pump (5 mL/min) Pump (5 mL/min) SGF/250 mL/100 rpm SGF/250 mL/100 rpm • FaSSIF/250 mL/50 rpm/pH • FaSSIF/250 mL/50 rpm/pH 6.5FaSSIF/pH 7.0 6.5FaSSIF/pH 7.0 • Sink/supersaturation • Sink/supersaturation compartment compartment 19
Case Study: Ketoconazole • Ketoconazole: Weak dibasic antifungal agent • pKa: 2.94, 6.51 • BCS II • Permeability: Caco-2 Peff=53x10 -6 cm/sec • Solubility: – Virtually insoluble at pH 5 or pH Solubility (mg/mL) higher 1.6 (FaSSGF) 9 – Detailed solubility profile (right) 3 (buffer) 1.8 3.5 (buffer) 0.7 • Administration: 4.5 (buffer) 0.25 – Exposure was well known as 5 (buffer) 0.1 being affected by elevated 6.5 (buffer) 0.007 stomach pH SGF 6 – Recommended to codose FaSSIF 0.02537 w/acidic cola drink
Ketoconazole Tablets: Transfer vs Two-Stage Transfer model Two-stage (1 vessel) (multicompartment) 600 600 Gastric % dissolved 2 nd stage volume, pH 6.5 100 100 500 500 Intestinal volume %Ketoconazole Dissolved 80 80 % Ketoconazole Dissolved 400 400 Volume (mL) Volume (mL) 300 300 60 60 Intestinal + sink 1 st stage 200 200 % dissolved 40 40 volume, pH 1.8 100 100 Two-stage % 20 20 0 0 dissolved Gastric volume 0 -100 0 -100 0 50 100 150 0 50 100 150 Time (min) Time (min) • Some precipitation observed in the transfer model; significant precipitation in two-stage dissolution • A small amount of precipitation was observed in fasted adult study (Psachoulias D, et al. Pharm Res. 2011;28(12):3145-3158. doi: 10.1007/s11095-011-0506-6)
Case Study: Dipyridamole • Inhibits thrombus formation (antiplatelet) • Free base with pKa of 6.4 • BCS Class II • Permeability: Estimated human Peff 1.5 (cm/sec x 10 -4 ) • Tablets: 25 mg, 50 mg, 75 mg • Recommended dose: 75-100 mg 4 times daily • Significantly decreased exposure with famotidine-treated healthy elderly patients pH Solubility (mg/mL) • The absolute bioavailability is 27 +/- 5.5% (range 11% – 44%) 3.5 2.2 4.2 0.5 5 0.0054 6 0.0010 7 0.0005 7.8 0.0006 SGF 8 FaSSIF 0.01148 Terhaag B, et al. Int J Clin Pharmacol Ther Toxicol . 1986;24(6):298-302. Glomme A, et al. J Pharm Sci. 2005;94(1):1-16.
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